The broad, long term objectives of this research proposal are to gain further knowledge on the mechanisms of thyroid hormone action and to improve our ability to diagnose and treat a group of conditions known as syndromes of generalized resistance to thyroid hormone (GRTH). In order to achieve these goals, I plan to study GRTH at the molecular level since most of, if not all, such patients are likely to have inherited defective thyroid hormone receptors. I have the largest collection of DNA, fibroblasts and available patients with GRTH making my ability to execute this project unique. Recently developed methods for the clinical diagnosis of these syndromes as well as the recent identification of the genes expressing thyroid hormone receptor proteins, allow the achievement of these objectives through the detailed study of these errors of nature. Aim 1 will determine the prevalence of GRTH in ADHD. Patients suspected with the diagnosis of GRTH are: (a) referred to our clinic or (b) hopefully identified through a neonatal screening program with the state of Illinois; or (c) by screening children with the attention deficit/hyperactive disorder (ADHD), a condition suspected of having a high incidence of GRTH. These patients are then admitted to the Clinical Research Center (CRC) to confirm the diagnosis. Aim 2 will assess the use of T3 in treatment of children with ADHD and GRTH. DNA from patients with clinically confirmed GRTH will be screened for abnormalities in the genes coding for the human thyroid hormone receptors (hTR). The physiological significance of the identified mutant hTR will be determined. Transcription and translation of the mutant gene will be done to allow assessment of the functional domains of the encoded molecules, namely, their thyroid hormone and DNA binding properties. As there are at least three different forms of TRs expressed in man (alphal, alpha2, and betal), the mechanism of action and interaction of these different receptors are unknown. By defining the mutations in patients with GRTH, this would contribute to the identification of physiologically relevant thyroid hormone receptor products and the position of amino acids important for the proper function of the DNA and hormone-binding domains.